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Abstract:

A SCCA-1 production inhibitor, comprising as an active ingredient, at
least one carboxamide derivative selected from the group consisting of
compounds represented by the following formula (I):
##STR00001##
wherein X is CR5 or N, R1, R4 and R5 each
independently represent hydrogen, C1-C4 alkyl or a
C1-C6 hydroxyalkyl group having 1-5 hydroxy groups, R2 and
R3 each independently represent hydrogen, C1-C4 alkyl or a
C1-C6 hydroxyalkyl group having 1-5 hydroxy groups, or each
represents a group --(CH2)n--, wherein n represents an integer
of 1 or 2, and may form a 5- to 6-membered ring together with the atoms
to which they are bonded and with the carbonyl group, allantoin, and
salts thereof.

Claims:

1. A method of inhibiting (Squamous Cell Carcinoma Antigen 1 production
inhibitor, comprising administering as an active ingredient to a subject
in need thereof, at least one carboxamide derivative selected from the
group consisting of compounds represented by the following formula (I):
##STR00005## wherein X is CR5 or N, R1, R4 and R5
each independently represent hydrogen, C1-C4 alkyl or a
C1-C6 hydroxyalkyl group having 1-5 hydroxy groups, R2 and
R3 each independently represent hydrogen, C1-C4 alkyl or a
C1-C6 hydroxyalkyl group having 1-5 hydroxy groups, or each
represents a group --(CH2)n--, wherein n represents an integer
of 1 or 2, and may form a 5- to 6-membered ring together with the atoms
to which they are bonded and with the carbonyl group, allantoin, and
salts thereof.

2. The method according to claim 1, wherein the carboxamide derivative is
one of the following: ##STR00006## or a salt thereof.

3. A method for prevention and/or treatment of a disease associated with
abnormal cell proliferation, comprising administering to a subject in
need thereof a pharmaceutical composition comprising a carboxamide
derivative according to claim 1 and/or a salt thereof as an active
ingredient.

4. A method for prevention and/or treatment of acanthosis, comprising
administering to a subject in need thereof a pharmaceutical composition
comprising a carboxamide derivative according to claim 1 claim 1 and/or a
salt thereof as an active ingredient.

[0003] SCCA is known to have accelerated expression not only in squamous
cell carcinoma, but according to research by the present inventors, also
in the upper layer of psoriatic epidermis (Non-patent document 3: Takeda
A. et al, J. Invest. Dermatol. (2002) 118(1), 147-154). Psoriasis is a
type of skin disease with high frequency, and may take the form of
chronic, relapsing inflammatory parakeratosis characterized by abnormal
proliferation and differentiation of epidermal cells and infiltration of
inflammatory cells. Psoriasis is believed to occur as a result of genetic
disposition and several environmental factors (Non-patent document 4:
Hopso-Havu et al. British Journal of Dermatology (1983) 109, 77-85).

[0004] SCCA is encoded by the two genes SCCA-1 and SCCA-2 situated in
tandem on chromosome 18q21.3. The proteins encoded thereby, SCCA-1 and
SCCA-2, are both proteins with molecular weights of approximately 45,000,
and while they have very high homology, their amino acid sequences differ
at the reactive sites, whereby their different functions are presumably
exhibited (Non-patent document 5: Schick et al. J. Biol. Chem. (1997)
27213, 1849-55).

[0005] The present inventors have conducted research with the aim of
elucidating the physiological mechanism of SCCA-1 and SCCA-2 in the
epidermis, and as a result we have obtained the knowledge that both SCCA
proteins are anti-apoptotic factors having effects of inhibiting cellular
apoptosis (Patent document 1: Japanese Unexamined Patent Publication No.
2005-281140).

[0006] The present inventors have also conducted research with the aim of
evaluating the sensitivity of skin, using SCCA-1 expression in particular
as an index, and as a result we have obtained the knowledge that SCCA-1
expression is increased 16-fold in atopic xeroderma, 90-fold in
light-exposed skin, 232-fold in pollen hypersensitive allergenic skin and
466-fold in psoriatic skin, compared to controls (Japanese Patent
Application No. 2006-075024).

[0007] The present inventors, having further researched the relationship
between cell proliferation and SCCA, and especially SCCA-1, have also
obtained the knowledge that: [0008] cell proliferation is activated in
high SCCA-expressing mice, [0009] acanthosis is seen in high
SCCA-expressing mice, [0010] a correlation exists between cell
proliferation and SCCA-1 expression in high SCCA-1-expressing cell lines,
and [0011] cell proliferation activity is reduced in SCCA knock-down cell
lines (Japanese Patent Application No. 2007-279024 and Journal of Cell
Biology, 172(7), 983-990 (2006)).

[0012] Thus, a substance that effectively inhibits production of SCCA, and
especially SCCA-1, is believed to be useful for prevention and/or
treatment of diseases associated with abnormal cell proliferation, and
diseases associated with increased SCCA-1 production.

[0020] The present inventors, as a result of focusing on the relationship
between cell proliferation and SCCA-1 and screening a large variety of
medicinal agents, have found that certain carboxyamide derivatives and/or
their salts significantly inhibit production of SCCA-1. The present
inventors have therefore concluded that these carboxyamide derivatives
and/or their salts are highly useful for prevention and/or treatment of
diseases associated with abnormal cell proliferation and diseases
associated with increased SCCA-1 production, due to their inhibitory
action on SCCA-1 production, and the invention has thereupon been
completed.

Means for Solving the Problems

[0021] The present invention encompasses the following aspects.

[0022] [1] A SCCA-1 (Squamous Cell Carcinoma Antigen 1) production
inhibitor, comprising as an active ingredient, at least one carboxyamide
derivative selected from the group consisting of compounds represented by
the following formula (I):

##STR00002##

(wherein X is CR5 or N,

[0023] R1, R4 and R5 each independently represent hydrogen,
C1-C4 alkyl or a C1-C6 hydroxyalkyl group having 1-5
hydroxy groups,

[0024] R2 and R3 each independently represent hydrogen,
C1-C4 alkyl or a C1-C6 hydroxyalkyl group having 1-5
hydroxy groups, or each represents a group --(CH2)n--, wherein
n represents an integer of 1 or 2, and may form a 5- to 6-membered ring
together with the atoms to which they are bonded and with the carbonyl
group),

[0025] allantoin, and salts thereof.

[0026] [2] A SCCA-1 production inhibitor according to claim 1, wherein the
carboxyamide derivative according to [1] above is one of the following:

##STR00003##

[0027] or a salt thereof.

[0028] [3] A pharmaceutical composition for prevention and/or treatment of
a disease associated with abnormal cell proliferation, comprising the
carboxyamide derivative according to [1] or [2] and/or a salt thereof as
an active ingredient.

[0029] [4] A pharmaceutical composition for prevention and/or treatment of
acanthosis, comprising a carboxyamide derivative according to [1] or [2]
and/or a salt thereof as an active ingredient.

[0031]FIG. 1 shows the SCCA-1 expression-inhibiting effects of different
carboxyamide derivatives in a cell line.

[0032]FIG. 2 shows the SCCA-1 expression-inhibiting effect of allantoin
in a cell line.

[0033]FIG. 3 shows the SCCA-1 expression-inhibiting effect of urea in a
cell line.

BEST MODE FOR CARRYING OUT THE INVENTION

[0034] A carboxyamide derivative and/or its salt according to the
invention is highly useful for inhibiting production of SCCA-1.
Specifically, it was found that addition of a carboxyamide derivative to
culture medium during culturing of human keratinocytes significantly
inhibits production of SCCA1. By inducing abnormal proliferation of
epidermal cells and culturing a three-dimensional skin model with notably
increased SCCA1 expression in carboxyamide derivative-containing medium,
it was confirmed that acanthosis can be prevented and ameliorated. In
addition, it was confirmed that by continuous application of the
carboxyamide derivative onto human skin, SCCA1 levels can be
significantly reduced in the applied sections.

[0035] Furthermore, upon examining the effect of carboxyamide derivatives
and/or their salts according to the invention on human skin, they were
found to be useful for inhibiting accelerated thickening of the epidermis
of human skin.

[0037] When the carboxyamide derivative represented by formula (I) of the
invention is a known substance, it may be easily synthesized by a known
method or easily purchased as a commercial product, or if it is a novel
compound, for example, it may be easily synthesized by a method known to
those skilled in the art.

[0039] The SCCA-1 production inhibitor and pharmaceutical composition of
the invention comprise a carboxyamide derivative and/or its salt, and a
pharmaceutically acceptable excipient and/or carrier. The pharmaceutical
composition comprises a carboxyamide derivative and/or its salt in an
amount effective to exhibit the function, and the content is, for
example, preferably 0.001-20.0 mass %, more preferably 0.01-10.0 mass %
and most preferably 0.2-10.0 mass % of the total pharmaceutical
composition, although this will vary depending on the purpose of use of
the pharmaceutical composition. When the carboxyamide derivative and/or
its salt is to be used in admixture, the upper limit for the total
content is preferably no greater than 20.0 mass % and even more
preferably no greater than 10.0 mass.

[0040] The SCCA-1 production inhibitor and pharmaceutical composition of
the invention may be in various dosage forms depending on the purpose,
and for example, it may be administered in oral form such as a tablet,
coated tablet, sugar-coated tablet, hard or soft gelatin capsule,
solution or suspension, in enteral form such as a suppository, in a
parenteral form such as an injection, or in external application form
such as a patch, ointment, cream or latex.

[0041] The SCCA-1 production inhibitor and pharmaceutical composition of
the invention may contain a pharmaceutically acceptable carrier as an
appropriate inorganic or organic solid or solution, for example, as
desired, together with the active ingredient. For example, it may contain
a diluent (lactose, dextrose, saccharose, mannitol, sorbitol, cellulose
or the like), a lubricant (silica, talc, or stearic acid or a salt
thereof such as magnesium stearate or calcium stearate), and/or
polyethylene glycol. A tablet may contain a binder (aluminum silicate
magnesium, starch, gelatin, tragacanth, methylcellulose, sodium
carboxymethylcellulose and/or polyvinylpyrrolidone, or the like), and if
desired a disintegrator (starch, agar, alginic acid or a salt thereof,
and/or an expandable mixture or the like), an absorbent, a coloring
agent, a flavoring and/or a sweetener, for example.

[0042] The SCCA-1 production inhibitor and pharmaceutical composition of
the invention may also contain a preservative, solubilizing agent,
stabilizer, moistening agent, emulsifier, sweetener, coloring agent or
flavoring agent, a salt for osmotic pressure variation, a buffering
agent, a coating agent or an antioxidant. The SCCA-1 production inhibitor
and pharmaceutical composition of the invention may further contain
substances with therapeutic value, such as active ingredients other than
the carboxyamide derivative and/or its salt according to the invention.

[0043] The method and amount fox use of the SCCA-1 production inhibitor
and pharmaceutical composition of the invention may be varied within a
wide range, and can be decided by a method known to a person in the
field. The method and amount for use are adjusted as necessary for each
individual specific case, in consideration of the route of
administration, the symptoms to be treated and the patient to be treated.
The dosage may vary according to the purpose of use and the dosage form
of the drug composition and on the body weight and body surface area of
the patient, but it is preferably a dosage of 0.1 μg-10,000 mg and
even more preferably 100 μg-1000 mg, per day. It may be administered
all at once or in divided doses, and the method of administration may be
oral or injection, or application.

[0055]FIG. 1 shows the results with addition of the compound
1-(2-hydroxyethyl)-2-imidazolidinone, 1-(2-hydroxyethyl)-2-pyrrolidone or
ethyleneurea. As a negative control, no drug was added, and as a positive
control there was added 1-piperidinepropionic acid (1-PP) (Japanese
Patent Application No. 2008-903571), which is known to have a gene
expression-inhibiting effect on SCAA-1 and SCAA-2. As shown in the graph,
a significant dose-dependent reduction in SCCA-1 gene expression was
seen. FIG. 2 and FIG. 3 show the results of adding allantoin and urea,
respectively, and similarly, a significant dose-dependent reduction in
SCCA-1 gene expression was seen.